Heterocyclic antituberculous compounds



Patented Jan. 5, 1954 UNITED STATES PATENT OFFICE HETEROCYCLIC ANTITUBERCULOUS COMPOUNDS J 01 n Alfred Aeschlimann, Montclair, and Arthur Stempel, River mann-La Roche Inc.,

tion of New J ersey Edge, N. J., assignors to Hoff- Nutley, N. J., a corpora- No' Drawing. Application J my 2, 1952 Serial No. 296,948

wherein R is hydrogen or a lower alkyl radical. The members of this class are antituberculous compounds, and are also useful as intermediates in the preparation of derivatives having utility as medicinals.

In general, the members of the above class can be made by reacting l-isonicotinyl hydrazine or a l-isonicotinyl-z lower alkyl-hydrazine with phosgene, and neutralizing the reaction mixture thus obtained.

The invention is further disclosed in the fol lowing examples, which are illustrative but not limitative thereof:

Example 1 To a stirred suspension of g. of monosodium urea in cc. of acetone, cc. of methyl isonicotinate were added. The temperature rose rapidly to about 40 C. An additional 10 cc. of acetone were added. The thick mixture was kept overnight at room temperature, filtered and washed with acetone. After dissolving the washed material in 250 cc. of water, the pH of the solution was 11.5. When neutralized to pH 5-6 with acetic acid, isonicotinyl urea crystallized, M. P. 233-236 C. with decomposition. After two recrystallizations from water, the melting point rose to 240-241 C. with decomposition.

A solution of 4 g. of isonicotin'yl urea in 110cc. of concentrated hydrochloric acid was cooled in an ice bath and a rapid stream of chlorine was passed through for 15 minutes. The solution was diluted with 500 cc. of water, cooled and neutralized with sodium carbonate. The chlorine-containing product that separated was filtered and dried in a vacuum desiccator. A solution of 3.1 g. of the chlorine-containing compound in 50 cc. of 5% NaOH was made and, after several minutes at room temperature, was neutralized with acetic acid. The solid that separated was filtered off and recrystallized from water to give 5-(4-pyridyl)-1,3,4-oxadiazol-2(3H)-one, M. P. 268-270 C. The formation of this product can 6 Claims. (Cl. 260295) be represented by the following formula scheme, in which the product in square brackets is a hypothetical intermediate Example 2 A solution of 10 g. of isonicotinyl hydrazine in cc. of water was cooled in an ice bath and a stream of'phosgene was passed through for 15 minutes. The solution was then diluted, neutralized with sodium. carbonate and filtered. The crude 5-(4-pyridyl)-1,3,4-oXadiazo1 2(3H)- one, melting at 270-272 C. with decomposition, was recrystallized from water or alcohol without significant change in'melting point. A mixed melting point with the product prepared in Example 1 showed no depression. The product of this example is formed according to the following formula scheme:

Example 3 A solution of 10 g. of-1-isonicotinyl-2-isopropy1 COC12 Similarly, by using other species of l-isonicotinyl-Z-lower alkyl-hydrazine as the starting materials in lieu of 1-isonicotiny1-2-isopropy1 hydrazine recited above, additional species of 3-lower alkyl 5 -(4-pyridyl) 1,3,4 oxadiazol- 2(3H)-one can be prepared, which latter have the same lower alkyl radical in the 3-position thereof as present in the 2-position of the substituted hydrazine starting material.

The l-isonicotinyl-Z-lower alkyl-hydrazine starting materials employed in this example are not part of the instant invention. In general, starting materials of this class can be prepared by reacting l-isonicotinyl hydrazine with a dialkyl ketone to yield a l-isonicotinyl-Z-lower alkylidene-hydrazine and catalytically hydrogenating the latter to produce a 1-isonicotinyl-2- lower alkyl-hydrazine. An alternative method of preparation comprises reacting a lower alkyl ester of isonicotinic acid with a lower alkyl hydrazine, the lower alkyl substituent in which latter is the same as that of the desired l-isonicotinyl-Z-lower alkyl-hydrazine.

Example 4 A mixture of 1 g. of 5-(4-pyridyl)-1,3,4-oxadiazol2(3H) -one and 4 cc. of aniline was heated to boiling for 34 minutes. After cooling, the reaction product, containing isonicotinic acid hydrazide, was slurried in ether and extracted with water. On addition of levulinic acid to the aqueous layer, -isonicotinyl hydrazonovaleric acid crystallized, M. P. 208209 C. (The last named compound is not part of our invention.)

Ehe reaction can be illustrated by the following formula scheme, in which R represents the radical attached to the amino group. In the immediately preceding paragraph, R represents phenyl. In the three paragraphs immediately following this formula scheme, R represents respectively, cyclohexyl, 2-ethylhexyl, and diethylaminoethyl.

A mixture of 1 g. of 5-(4-pyridyl) -1,3,4-oxadiazo1-2(3H) -one and 5 cc. of cyclohexylamine was refluxed for 15 minutes. After cooling, the slurry produced, containing isonicotinic acid hydrazide,

was partitioned between water and ether. The

1 Number A solution of 2 g. of 5-(4-pyridyl)-1,3,4-oxacliazol-2(3H)-one in 20 cc. of diethylaminoethylamine was refluxed for 1 hour. After excess diethylaminoethylamine was distilled oil in vacuo, the residue crystallized. Recrystallization from acetonitrile gave 750 mg. of isonicotinic acid hydrazide, M. P. 160-l65 C. Further recrystallization brought the melting point to 166-163 C. On reaction with levulinic acid the hydrazide gave 'y-isonicotinyl hydrazonovaleric acid, M. P. 2l0-212 C.

Example 5 A mixture of 3 g. of 5-(4-pyridyl)-1,3,4-oxadiazol-2(3H) -one in 50 cc. of methanol containing 1.5 cc. of hydrazine was refluxed for 1 hour. The product, 1 isonicotinyl carbohydrazide, crystallized from the hot solution, M. P. 215-216 C. This product, which can be represented by the formula is also an antituberculous compound.

The formation of the above product can be represented by the following formula scheme:

References Cited in the file of this patent FOREIGN PATENTS Country Date '730,292 Germany Jan. 14, 1943 OTHER REFERENCES 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF 5-(4-PYRIDYL)-1,3,4-OXADIAZOL-2(3H)ONE AND 3-LOWER ALKYL-5-(4-PYRIDYL)-1,3,4-OXADIAZOL-2(3H)-ONE.
 5. 1-ISONICOTINYL-CARBOHYDRAZIDE.
 6. A PROCESS OF PREPARING ISONICOTINIC ACID HYDRAZIDE WHICH COMPRISES REACTING 5-(4-PYRIDYL)1,3,4-OXADIAZOL-2(3H) -ONE WITH A PRIMARY AMINE, AT A REACTION TEMPERATURE ABOVE ABOUT 130* C. 